The strategic goal of this project has for almost 20 years been to define the ontogeny of neuroendocrine carcinomas of the pancreas that develop via a series of stepwise transitions, inferred to reflect the acquisition of necessary capabilities to manifest a tumor, the so-called 'hallmarks of cancer'. One can foresee it will be possible to identify the regulatory determinants and functional effectors that dictate and underlay each of the stepwise transitions from normality to lethal cancer for this prototypical pathway, establishing a conceptual framework from which to consider pathways to cancer in other mouse models and in human cancers. The general approach involves a transgenic mouse model, RIP-Tag2, which presents the opportunity to follow the genesis of tumors from their earliest beginnings in the pancreatic islets up through their lethal culmination as invasive cancers. The pathway can be readily probed and perturbed with specifically altered genes or pharmacological inhibitors, to identify critical functional determinants and clarify mechanistic principles. The specific focus of this renewal is to investigate regulatory determinants of the 'invasive switch' that is activated during pancreatic tumorigenesis. Functional tests will assess the hypothesis that the invasive switch is mediated in significant part by an intracellular signaling circuit emanating from the IGF-1 receptor tyrosine kinase, as well as the ancillary possibility that members of the EGF receptor family are contributing to this or other capabilities that determine pancreatic tumorigenesis. Critical nodal points in these signaling pathways will be perturbed both pharmacologically and genetically, aiming to prevent progression to the invasive growth phenotype, or revert it, thereby clarifying their importance as regulators of invasion as well as other hallmark capabilities that enable tumorigenesis, potentially guiding therapeutic applications. The specific aims are to Aim 1. Assess the causality of IGF-1 receptor signaling for the invasive switch during islet tumorigenesis, and begin to define the critical downstream effectors of its pro-invasive signaling. Aim 2. Interfere with signaling by candidate EGF ligands and their multiple receptors to address the hypothesis that members of the EGF ligand/receptor family are functionally contributing to the regulation of islet tumorigenesis, including the invasive growth capability. Aim 3. Assess roles of IFG1R and EGFR-family signaling of the invasive switch in pancreatic ductal adenocarcinoma using a mouse model that recapitulates the human disease's lesional progression and oncogenic events.